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TPS164 Background: Combretastatin A1 diphosphate (CA1P, OXi4503) is a novel vascular disrupting agent (VDA) that is a reversible tubulin-binding agent with direct cytotoxic activity when bioactivated to its reactive orthoquinone metabolite. Several oxidative enzymes have been shown to catalyze this reaction including myeloperoxidase (MPO), tyrosinase, and hepatic peroxidases. Based on these findings it is expected that OXi4503 should be more active in tissues and tumors containing high levels of these and other oxidative enzymes. Nonclinical blood flow studies in tumor-bearing SCID mice showed that OXi4503 treatment (1 to 50 mg/kg) produced a decrease in tumor-associated blood volume. A dose of 50 mg/kg resulted in approximately 100% reduction in tumor vascular volume, compared with control mice. Tumor growth inhibition has been observed in single- and repeat-dose xenograft studies in multiple tumor models including breast cancer (MDA-MB-231), colorectal, renal (Caki-1), hepatocellular (HEP-G2), melanoma ...

Purpose: A rat model was developed to enable direct administration of hyperpolarized 13C-labeled molecules into a tumorsupplying artery for magnetic resonance spectroscopy (MRS) studies of tumor metabolism. Methods: Rat P22 sarcomas were implanted into the right inguinal fat pad of BDIX rats such that the developing tumors received their principle blood supply directly from the right superior epigastric artery. Hyperpolarized 13C-molecules were either infused directly to the tumor through the epigastric artery or systemically through the contralateral femoral vein. Spectroscopic data were obtained on a 7 Tesla preclinical scanner. Results: Intra-arterial infusion of hyperpolarized 13C-pyruvate increased the pyruvate tumor signal by a factor of 4.6, compared with intravenous infusion, despite an approximately 7 times smaller total dose to the rat. Hyperpolarized glucose signal was detected at near-physiological systemic blood concentration. Pyruvate to lactate but not glucose to lactate metabolism was detected in the tumor. Hyperpolarized 13Clabeled combretastatin A1 diphosphate, a tumor vascular disrupting agent, showed an in vivo signal in the tumor. Conclusions: The model maximizes tumor substrate/drug delivery and minimizes T1 relaxation signal losses in addition to systemic toxicity. Therefore, it permits metabolic studies of hyperpolarized substrates with relatively short T1 and opens up the possibility for preclinical studies of hyperpolarized drug molecules.